Project Summary/Abstract Hearing loss affects most individuals, with increasing severity as we age. The primary cause is the loss of sensory hair cells within the organ of Corti. Hair cells do not regenerate and so what you are born with must last a lifetime, an increasingly difficult task given the constant assault from electronics, machinery, and ototoxic drugs. Efforts to induce regeneration of hair cells, while highly promising, have run into numerous problems. In early development, supporting cells of the organ of Corti can be chemically induced to transdifferentiate to hair cells, thus achieving limited regeneration. As supporting cells mature, they lose their plasticity and are no longer able to transdifferentiate. To make regeneration of hair cells and restoration of hearing feasible, we must overcome this barrier. The loss of plasticity during development is a common dilemma in a variety of cell types, and has become increasingly attributed to epigenetic mechanisms. In this proposal, I investigate the role of the epigenetic modifiers Prc2 and Kdm6b in the plasticity of early support cells of the cochlea and their subsequent loss of plasticity. To do so I conduct inhibitor studies, ChIP-seq experiments, and use mouse genetic models. My findings will help us understand the mechanisms blocking regeneration of hair cells, and expand our general understanding of how cell types are established. Identifying the epigenetic regulators, Prc2 and Kdm6b, responsible for supporting cell plasticity would move the field past this barrier to regeneration, and provide the targets for future drug discovery.